Our goal is to investigate whether in Hodgkins lymphoma (HL) molecular markers can inform decisions regarding the duration or intensity of therapy and to determine whether vaccination and/or adoptive immunotherapy strategies may ultimately allow standard therapies to be shortened or de-escalated in some patients. HL is particularly well suited for these investigations in several regards. With present therapies, some patients fail while others are cured yet continue to receive treatment for weeks or months afterwards. New prognostic markers and techniques to monitor tumor response may help identify those who are likely to be cured and should ultimately receive less therapy and those who are not yet cured and may need high dose or experimental therapies. Similarly, new therapeutic modalities to augment cytotoxic chemotherapy or radiation therapy are attractive insofar as they may result in cures in patients who are presently not cured or might partially substitute for these therapies in patients who are being cured and so allow a reduction in toxicity. Epstein-Barr virus (EBV) is present in the malignant cells of HL in many patients. Measurement of viral DNA may be used in tumor monitoring. EBV DNA is detectable in plasma from patients with EBV- associated tumors including HL and has been reported to be used in therapeutic monitoring of post-transplant lymphoma and nasopharyngeal carcinoma. In the first Specific Aim, we seek to characterize the origins of viral DNA detected in plasma from patients with HL, determine the association with the presence of viral nucleic acid and protein in the tumor, and assess the possible utility of viral DNA detection in therapeutic monitoring. These studies will involve prospective collections from the Children's Oncology Group (COG) and from patients treated at the Johns Hopkins Hospital, the Dana Farber Cancer Institute, and the Massachusetts General Hospital. The 2nd and 3rd Specific Aims involve immunotherapeutic strategies. The EBV proteins LMP2 and EBNAI are both expressed in EBV+ HL tumor cells and are established as targets for CD8(+) cytotoxic T cells and CD4(+) helper T cells, respectively. Both therapeutic approaches will be investigated in association with high dose therapy and autologous peripheral stem cell rescue insofar as this has emerged as the standard salvage therapy for HL patients and reduces tumor bulk and tumor-associated cytokines, chemokines and other molecules that may compromise the efficacy of the immune response. In the second Specific Aim, a therapeutic vaccine strategy in the treatment of EBV+ HL will be investigated. A phase I/pilot trial in patients with EBV+ HL will involve vaccination with an irradiated LMP2/EBNAI/GM-CSF expressing cell line. The goal of the trial will be to establish efficacy in achieving immunologic response endpoints and to assess safety. In the third Specific Aim, an adoptive cellular immuno-therapy with autologous T cells specific for EBV proteins expressed in HL in the context of high dose therapy with peripheral stem cell transplantation. Specific Aims 2 and 3 will be conducted at the Johns Hopkins Hospital, the Brigham and Women's Hospital and the Massachusetts General Hospital. These studies should illuminate the use of new approaches to tumor monitoring and immunotherapy. Although focused on EBV+ HL, the approaches to monitoring tumor-specific DNA in serum and the use of antigen-specific targeted immune interventions should be generalizable as specific molecular markers for Hodgkins and other lymphomas are identified.